Metformin hydrochloride is an orally-administered antihyperglycemic agent, used in the management of non-insulin-dependent diabetes mellitus.
Metformin hydrochloride tablets are sold in strengths of 500 mg, 850 mg and 1000 mg in the United States and elsewhere under the tradename Glucophage(trademark).
Glucophage(trademark) tablets are made as core tablets comprising metformin hydrochloride, povidone and magnesium stearate, which are then film-coated. For the 1000 mg strength of Glucophage(trademark) tablets, the weight per tablet is about 1070 mg, of which the weight of the core tablet before coating is about 1050 mg.
The function of the magnesium stearate in the core tablet is to act as a lubricant to prevent sticking to the tooling (punches and dies) in the tabletting process. The function of the povidone is to act as a binder to cause the metformin hydrochloride to bind into a sufficiently hard tablet under compression in the tabletting process.
In general, pharmaceutical tablets are made either by a xe2x80x9cdry-mixxe2x80x9d process or a xe2x80x9cwet-granulationxe2x80x9d process.
In a dry-mix process, ingredients are mixed together in dry form (i.e. without addition of water or an organic solvent) and the mixture is then either directly compressed into tablets, or alternatively compacted into slugs, which are then ground up into granules, following which the granules are then compressed into tablets.
(trademark)-Registered trademark
A dry-mix process is possible only when either:
i) the active ingredient itself has suitable binding properties to enable binding into hard tablets on compression, or
ii) a sufficient quantity of a dry-mix binder can be mixed with the active, so that the mixture will form hard tablets on compression. There are numerous inactive ingredients that are frequently used as dry-mix binders, such as, for example, microcrystalline cellulose, dicalcium phosphate and lactose. Microcrystalline cellulose is generally considered to be the best dry-mix binder, in that it enables increased tablet hardness when used in relatively small amount.
Metformin hydrochloride is an active ingredient which does not have good binding properties. Hence, dry-mix tablets are only possible if enough of a dry-mix binder can be added to enable tablets of adequate hardness to be made. For metformin hydrochloride, the amount of microcrystalline cellulose that needs to be added to enable tablets of adequate hardness is about 500 mg or more per 1000 mg of metformin hydrochloride. A tablet comprising 1000 mg of metformin hydrochloride would thus need to weigh about 1500 mg or more, and would be of size difficult to swallow. It is apparently for this reason that Glucophage(trademark) tablets are not made by the dry-mix approach.
When a dry-mix approach cannot be used, the alternative is xe2x80x9cwet granulationxe2x80x9d.
This approach uses a binder that is more effective than microcrystalline cellulose on an equal-weight basis, but such binders need to be activated by use of a solvent. That is to say, the binder and water or organic solvent are mixed with the active ingredient, with or without other excipients (inactive ingredients) to form a wet mass, the wet mass is dried to evaporate the solvent, the dried mass is ground up into granules. Other excipients (including a lubricant) are then added, and the mixture is compressed into tablets. Commonly used wet-granulation binders are povidone, hydroxypropyl cellulose, pregelatinized starch and gelatin.
Glucophage(trademark) tablets are made by the wet-granulation approach using povidone as the binder, and magnesium stearate as lubricant. This approach enables tablets of adequate hardness with minimum weight and size. However, this approach has the disadvantage of being relatively complex, in that the process requires the steps of adding water or another solvent to activate the binder and evaporating the solvent.
In light of this prior art, the object of the present invention is to enable the manufacture of metformin hydrochloride tablets of relatively small size by a dry-mix process; that is to say, a process that does not include the addition of water or another solvent to activate the binder.
It has surprisingly been found that metformin hydrochloride tablets of relatively small size and good hardness can be made by a dry-mix process using methylcellulose as a dry-mix binder, provided that no stearate is added, or alternatively the amount of stearate that is added is under 0.6% by weight.